Our goal is to develop gene-therapy approaches which can effectively treat sickle cell diseases and other severe hemoglobinopathies. We have recently published techniques for inserting new genes into the bone marrow of intact mice. Genes conferring resistance to methotrexate were inserted and cells carrying these new genes came to predominate in the marrow after treatment of the animals with moderate levels of methotrexate. This is the first successful use of gene-therapy type techniques in intact animals. More recently we have shown that human globin genes can be introduced into the mouse cells in concert with the genes conferring drug resistance. We will use a variety of experimental approaches in mice and rhesus monkeys to develop techniques which can alter the genetic information in hematopoietics stem-cells of patients with severe life-threatening hemoglobinopathies in such a manner that increased levels of normal hemoglobins will be produced.